Betulinic acid is useful as a therapeutic agent. For example, Pisha, E. et al., (1995) J. M. Nature Medicine, 1, 1046-1051 disclose that betulinic acid has antitumor activity against melanoma, e.g., MEL-1, MEL-2 and MEL4. In addition, Fujioka, T. et al., J. Nat. Prod., (1994) 57, 243-247 discloses that betulinic acid has anti-HIV activity in H9 lymphocytic cells.
Betulinic acid can be manufactured from betulin, which is present in large quantities in the outer birch bark of numerous species of birch trees. For example, a single paper mill in northern Minnesota generates nearly 30-70 tons of birch bark per day. Approximately 230,000 tons of birch bark are generated per year. Outer bark of Betula verrucosa (European commercial birth tree) contains nearly 25% betulin (Rainer Ekman, 1983, Horzforschung 37, 205-211). The outer bark of Betula paparifera (commercial birch of northern U.S. and Canada) contains nearly 5-18% betulin (see, U.S. Pat. Ser. No. 09/371,298). As such, vast quantities of betulin are available.
U.S. Pat. No. 5,804,575 issued to Pezzuto et al. discloses a five-step process for the synthesis of betulinic acid from betulin. Due to the length of time required to carry out this process and the yield it provides, it is not ideal for the commercial scale (e.g., kilogram) production of betulinic acid. Additionally, the process uses solvents and reagents that are hazardous and expensive, and the disclosed purification steps are not feasible on a commercial scale.
The first step in the preparation of betulinic acid from betulin-3-acetate was described by Ruzichka et al. (Helv. Chim. Acta., 21, 1706-1715 (1938)). The main obstacle for employing this method is the preparation of starting material (i.e., betulin-3-acetate). The selectivity of the hydrolysis of betulin-3, 28-diacetate with potassium hydroxide provided about 60% betulin-3-acetate. The use of magnesium alcoholates (Yao-Chang Xu et al., J. Org. Chem., 61, 9086-9089 (1996)) in the selective deprotection of betulin-3,28-diacetate (Yao-Chang Xu et al., J. Org. Chem., 61, 9086-9089 (1996)) has several serious drawbacks. The selectivity of this process is about 81%. Additionally, the cost of magnesium alcobolates is fairly high. As such, this method is not attractive for the commercial scale production of betulinic acid.
Thus, there exists a need for improved methods for preparing betulinic acid and synthetic precursors thereof. Such improved methods should require less time, should provide a higher overall yield, should be more cost effective (i.e., should require less expensive reagents and solvents) than known procedures, or should satisfy the contemporary industrial demands from both safety and environmental points of view.
The present invention provides a method for preparing betulinic acid and precursors thereof. The methods of the present invention require less time and require reagents that are less expensive, less toxic, or less flammable than known methods for preparing betulinic acid and the precursors thereof.
The present invention provides a process for preparing a compound of formula III 
comprising alcoholyzing a compound of formula II 
wherein each R1 and R2 are each independently a suitable organic group.
The present invention also provides a process for preparing a compound of formula V 
comprising:
(1) acylating a compound of formula I 
to provide a compound of formula II 
wherein each R1 and R2 are each independently a suitable organic group;
(2) alcoholyzing a compound of formula II to provide a compound of formula III; 
(3) oxidizing the compound of formula III to provide a compound of formula VI; 
(4) oxidizing the compound of formula VI to provide a compound of formula IV; and 
(5) deprotecting the compound of formula IV to provide the compound of formula V.
The invention also provides novel compounds disclosed herein, as well as methods for their synthesis.